抗生素英文课件精品 beta lactam antibiotics and other cell wall synthesis inhibitors

BETALACTAMANTIBIOTICSANDOTHERCELLWALLSYNTHESISINHIBITORSMa ShielaCano Guiking M D PENICILLINSI CLASSIFICATIONA PenicillinaseResistant AntistaphylococcalPenicillins 1 Methicillin Staphcillin 2 Nafcillin Unipen Nafcil Nallpen 3 Isoxazolylpenicillinsa Oxacillinb Cloxacillinc Dicloxacillind Flucloxacillin B Penicillinase Susceptible1 Narrow Spectruma Benzylpenicillin PenicillinGb Phenoxymethylpenicillin PenicillinV2 ExtendedSpectrumA Aminopenicillinsa 1Ampicillina 2Estersa 2 1 Bacampicillina 2 2 Pivampicillina 2 3 Talampicillina 3 Amoxicillin B Carboxypenicillinsa 1Carbenicillina 1 1 Indanylcarbenicilline gGeopena 1 2 Disodiumcarbenicilline g Pyopena 2 Ticarcillina 3 TemocillinC Ureido penicillinsc 1 Mezlocillinc 2 Azlocillinc 3 Piperacillinc 4 Apalcillin II GENERALPROPERTIESA ChemicalPropertiesPenicillinsarederivativesofbenzylpenicillin fromwhichthemethylbenzeneradicalissplitoffbyamidaseproducing6 aminopenicillanicacid theparentcompoundofallsemisyntheticpenicillins Thecompoundconsistsof2basicstructures 1ThiazolidineRing A 2 Beta LactamRing B SiteofactionofBeta lactamase SiteofactionofAmidase Siteofattachmentofsidechain whichdeterminesmanyoftheantibacterialandpharmacologiccharacteristicsofaderivative spectrumandpenicillin resistance MechanismsofAction Specific inhibitthelaststepinthepeptidoglycansynthesisofthecellwallUnderlying 1 inhibitionoftranspeptidaseenzymes2 activationofpenicillinbindingproteins PBPs 3 activationofautolysins mureinhydrolases C MechanismsofResistance1 inactivationofantibioticbyBetalactamases2 modificationofPBPs3 impairedpenetrationofdrugtotargetPBPs4 presenceofaneffluxpumpKinetics absorptionvarywiththepreparationdependingontheiracidstabilityandproteinbinding absorptionofmostoralpenicillins exceptamoxicillin impairedbyfoodanddrugsshouldbegiven1 2hoursbeforeoraftermeal parenteral completeandrapid cannotpenetratetheblood brainbarrier but50 oftheplasmaconcentrationcanpassthroughinthepresenceofinflammation Probenecidandcertainorganicacidscaninhibittransferfromcerebrospinalfluid CSF tobloodstream mayleadtoincreaseCSFlevel Metabolizedbythelivertopenicillanic penicillenicacid penicillamine penicilloicacidandotherpenicilloylderivatives allergenicmetabolites Excretedprimarilybythekidneys 90 tubularsecretion 10 glomerularfiltration smallamountthroughbileandfeces sputumandmilk renalexcretioninhibitedbyprobenecid E AdverseEffects 1 Hypersensitivityreactionsmostcommonadverseeffects causethehighestincidenceofantibioticallergya majorantigenicdeterminant penicilloylmetaboliteskintesting penicilloylpolylysine PPL b Signsandsymptoms variedskinrashesandpurpuricreactions angioedemaandanyaphylacticreactions fever eosinophilia interstitialnephritis 2 Gastrointestinaldisturbancesafteroraladministration3 ConvulsionsfollowingrapidIVadministration4 Accidentalinjectionintothesciaticnerve severepainandnervedysfunctionpersistingforweeks5 Chronicusemaycause hepatitisovergrowthofminor atypicalorganismsfollowinguseofbroadspectrumpreparations 6 Specifictoxicities a ProcainePenicillinGafteraccidentalIVinjection pulmonaryembolismacutepsychoticreactionsb OxacillinandNafcillinhepatitisgranulocytopenia bonemarrowdepressionc DisodiumCarbenicillinandhighdosePenicillinGNa hypernatermiad PenicillinGPotassiumhyperkalemiawithhighdoses e PenicillinGSodiumJarisch herxheimerreactionwithhighdosesinsecondarysyphilisf CarbenicillinandTicarcillinbleedingdiathesisg Methicillininterstitialnephritish Ampicillinassociatedwithpseudomembranouscolitis III INDIVIDUALAGENTSA PenicillinG1 AntimicrobialSpectrum Streptococci meningococci enterococci pen susceptiblepneumococci non Blactamaseproducingstaph Treponema spirochetes B anthracis Clostridium Actinomyces G rodsandnonBlactamaseproducingG anaerobicorganisms2 Kinetics 1 3oforaldoseabsorbedfromintestinaltractrapidly foodimpairabsorption maximalconcentration 30 60min intravenousa AqueousPenicillinG peakin15 30min T 0 5 2hrs intramuscularB ProcainePenicillinGpeakin1 3hrs T1 2 12hrs C BenzathinePenicillinGmeandurationofantimicrobialactivity 26days 60 albuminbound widelydistributedtothetissuesandbodyfluids doesnotreadilyenterthecerebrospinalfluidwhenmeningesarenotinflamed probenecidanduremiainhibitsactivetransportsecretionintothebloodstream Preparations InternationalUnits measureofstrengthOralPreparations PenicillinGSodiumPenicillinGPotassiumParenteralPreparations1 shortactinga aqueousPenicillinGPotassium 1 7meqK 1M u b aqueousPenicillinGSodium 2 4 meqNa 1M u 2 longactinga ProcainePenicillinG 300 000 600 000 u 120mgprocaine vialb BenzathinePenicillinG 600 000 u 1 2M u vial 4 DosesandTherapeuticUsesa AqueousPenicillinGChild mildinfections 50 000 u 100 000 u kg dayinequallydividedDosesevery4 6hrs for7daysSevereinfections 200 000 u 600 000 u kg dayinequallydividedDosesevery2 6hrs for14days a ProcainePenicillinG 300 000 600 000 u IMODorBIDfor7daysforAdultsb BenzathinePenicillinG 1 2million 2 4 u IMmonthlySyphilis lessthan1yearduration 2 4M u IM Probenicid1gm dayfor10daysor2 4M u BenzathinePenicillinGIMsingledoselatelatent complicated 20M u aqueousPenicillinG dayfor10dayscongenitalsyphilis 50 000 u kg dayaqueousPenicillinGfor10days StaphylococcalinfectionsGram anaerobesMeningococcalinfectionsGonococcalinfectionsCarrierstatediphtheriaOtherunusualinfections actinomycosis Anthrax ratbitefever listeria pasteurella lymedisease erysipeloidProphylaxis recurrencesofstreptococcal rheumaticfever gonorrhea syphilis bacterialendocarditis D PenicillinVOralformindicatedonlyinminorinfectionsRelativepoorbioavailability needfordosing4xadayGram aerobicactivitiessimilartoPenicillinG5 10 xlessactiveagainstgram microbes esp Neisseriaandcertainanaerobesbetterabsorbedfromthegastrointestinaltractbecauseofbetteracidicstability D Ampicillin1 MicrobialSpectrumSomewhatlessactivethanPenicillinGagainstgram cocciEnterococcalgrp Dandviridansgrp Ofstreptococci Listeriamonocytogenes H influenzaEffectiveforShigellosisShouldnotbeusedforuncomplicatedsalmonellagastroenteritis mayprolongthecarrierstate 2 Kinetics GastricacidstableandwellabsorbedfromthegastrointestinaltractOrallyabsorbeddrugpeaksin2hrs Intramuscularadministereddrugpeaksin1hourMainlyexcretedbythekidneys alsothruthebileandfecesUndergoesenterohepaticcirculationOtherkineticpropertiessimilartoPenicillinGSodium 3 AdverseEffects Ampicillinskinrash occursin7 8 otherssimilartoPenG4 Preparationsa OralCapsules 250 500mgSuspension 125mg 250mg 5mlDrops 100mg mlb parenteral250mg 500mg mlvial 5 Dosesa mildinfectionsNewborn 25 50mgevery12hrs Child 50 100mg kg din4 6divideddosesAdult 1 4gm dayb severeinfectionsChild 200 600mg kg dayAdult 6 12gm dayE EstersofAmpicillinNoinherentantimicrobialactivityasesters butpharmacologicallyactivefollowinghydrolysistoAmpicillin50 higherbloodconcentrationthanAmpicillinandAmoxicillin F AmoxicillinCloselyrelatedtoAmpicillininchemicalandpharmacologicpropertiesMorerapidlyandcompletelyabsorbedfromgastrointestinaltractAttainshigherserumlevelsthanampicillin G CARBOXYPENICILLINSANDUREIDOPENICILLINS1 AntimicrobialSpectrumGram aerobesPseudomonasaeroginosaBacteroidesfragilis butinhigheramount doseCarboxypenicillins certainindole ProteusUreidopenicillins KlebsiellaAzlocillin 10 xmoreactivethancarbenicillinagainstPseudomonas 2 Preparationsa CarbenicillinDisodiumsalt containsapproximately5meqsodium gmforparenteraladministrationIndanylesters 500mgtabletsb UreidopenicillinsParenteralpreparations H Penicillinase Resistant1 Methicillin 15 80 xmoreactiveagainstpenicillinaseproducingmicrobesthanPenicillinG onlyparenterallyavailable currentlymanyresistantstrainsofStaph Aureushaveemerged nolongerusedbecauseofnephrotoxicity2 Nafcillin slightlymoreactivethanCloxacillinagainstpenicillinaseproducingStaph Aureus availableinoralandparenteralpreparations GITabsorptioniserratic3 IsoxazolylPenicillinsStableingastricacidandadequatelyabsorbedafteroraladministrationDicloxacillinismostactiveagainstpenicillinaseproducingStaph AureusAvailableinoralandparenteralpreparations CEPHALOSPORINSI CLASSIFICATIONA FirstGeneration1 Cephaloridine Loridine Ceporan2 Cephalothin Keflin3 Cephalexin Keflex Ceporex4 Cefazolin Cefacidal5 Cephradine Velosef6 Cepharpirin Cefadyl7 Cephadroxil Doricef Cefamox B SecondGeneration1 Cefaclor Ceclor2 Cefoxitin Mefoxin3 Cefuroxime Zinacef Zinnat4 Cefonicid Monocid5 Cefotetan Cefotan6 Cefamdandole Mandol7 Cefprozil Cefzil8 Loracarbef Lorabid9 Cefmetazole Zefazone10 Ceforanide C ThirdGeneration1 Cefotaxime Claforan2 Cefoperazone Cefobid3 Moxolactam Moxam4 Ceftizoxime Cefizox5 Ceftriaxone Rocephin6 Ceftazidime Fortum7 Cefotiam Ceradolan8 Cefixime Suprax9 Cefetamet Globocef10 Cefpodoxime Vantin11 Ceftibuten Cedax12 Cefdinir Omnicef13 Cefditoren D FourthGeneration1 Cefepime Maxipime2 Cefpirome CefromII BASISFORCLASSIFICATIONA AntimicrobialSpectrumB PharmacokineticProperties III GENERALPROPERTIESA Chemistry7 aminocephalosporanicacid parentcompoundcontainsanR2thatmakesthecompoundstableindiluteacidandhighlypenicillinaseresistant MW 400 450 Solubletowaterandrelativelystabletophandtemperaturechanges C7modificationsalterantibacterialactivityC3substituteschangemetabolismandkineticpropertiesB MECHANISMOFACTIONANDRESISTANCESimilartopenicillinsC AntimicrobialSpectrumGenerallybroaderspectrumthanPenicillinsGenerallymoreeffectivethanPenicillinsagainstB lactamase producingmicrobes exceptenterococci Methicillin resistantStaph aureusandStaph epidermis D SPECIFICGROUPS INDIVIDUALAGENTS1 FIRSTGENERATIONGoodactivityagainstgram andmodestagainstgram microbesPenetrationofthecerebrospinalfluid CSF isinadequateUTI minorstaphlesions minorpolymicrobialinfections cellulitis softtissueabscessNotusedinserioussystemicinfections 2 SECONDGENERATIONBetteractivityagainstanaerobesandgram aerobesOnlyCefuroximecanproducesufficientCSFlevelSinusitis otitis LRTI mixedanaerobicinfectionssuchasperitonitis diverticulitis 3 THIRDGENERATIONGenerallylessactivethanthefirstgenerationagainstgram coccibutmostactiveagainstgram includingB lactamase producingstrainsCefoperazone Ceftazidime moreactive againstPseudomonas Activeagainstanaerobes Cefoperazone CefotaximeCeftizoxime Moxolactam B fragilisCefoperazoneProbeneciddoesnotaffectrenalexcretionCrossBBBexceptCefoperazone Cefixime CeftibutenandCefpodoximeproxetil Ceftriaxone 125mginj Cefixime single400mgoraldose N gonorrheaCefoperazone T1 2 2hrs 25 100mg kg dinjectedq8 12hrsCefixime200mgorallytwiceadayor400mgODCefpodoximeproxetilshouldbeusedincombinationwithaminoglycosideforthetreatmentofmeningitiscausedbyP aeruginosa 4 FOURTHGENERATIONMoreresistanttohydrolysisbychromosomalbetalactamases eg Thoseproducedbyenterobacter GoodactivityagainstP aeruginosa enterobacteriaceae staph aureus S pneumoniaeHighlyactiveagainstHaemophilus NeisseriaPenetrateswellintoCSFClearedbykidneysT1 2 2hrsGoodactivityagainstmostpenicillinresistantstrainsofstreptococciUsefulinthetreatmentofenterobacterinfections E ADVERSEEFFECTS1 Allergy2 Toxicity 3 Renaltoxicity interstitialnephritisandeventubularnecrosisCephalosporinthatcontainsamethylthiotetrazolegroup Cefamandole Cefmetazole Cefotetan Cefoperazone causedisulfiramlikereactions hypoprothrombinemiaandbleedingdisorders Antidote VitK 10mg2x weekMoxolactam interfereswithplateletfunction severebleeding4 Superinfection MONOBACTAMSMonocyclicbetalactamringResistanttoB lactamaseActiveagainstgram rodsincludingPseudomonasandSerratiaAztreonam resemblesaminoglycosidesinspectrumofactivityGiven1 2gIVq8hrs T1 2 1 2hrs BETALACTAMASEINHIBITORS CLAVULANICACID SULBACTAM TAZOBACTAM ResembleB lactammoleculesBindtoBeta lactamase inactivatethemandpreventthedestructionSynergisticwithotherbeta lactamsA ClavulanicAcid producedbyS Clavuligerulpotentntinhibitorofbeta lactamases plasmidencoded weakantibacterialactioncombinedwithAmoxicillin Augmentin orTicarcillin Timentin thecombinationwidenstheantimicrobialspectrumB SulbactamPivoxilandAmpicillin Unasyn C TazobactamandPiperacillin Tazocin CARBAPENEMS structurallyrelatedtoBetalactamantibiotics1 Imipenem gram rods gram org excessiveinrenalfailure seizures2 Meropenem slightlygreateractivityagainstgram aerobesdoesnotrequireaninhibitorpenetratesCSF1gq8hrs ERTAPENEM LessactivethanmeropenemorimipenemagainstPseudomonasaeruginosaandacinetobacterspecies Itisnotdegradedbyrenaldehydropeptidase OTHERCELLWALLSYNTHESISINHIBITORS1 VANCOMYCINGram staphWatersolubleandquitestableMOA InhibitscellwallsynthesisbybindingfirmlytoD Ala D AlaterminusofnascentpeptidoglycanpentapeptideResistance modificationoftheD Ala D AlabindingsiteofthepeptidoglycanbuildingblockinwhichtheterminalD AlaisreplacedbyD lactateresultingtolossofacriticalHbondthatfacilitateshighaffinitybindingofvancomycintoitstargetandlossofactivity SynergisticwithgentamicinandStreptomycinagainstE faeciumandE faecalisstrainsthatdonotexhibithighlevelsofaminoglycosideresistancePoorlyabosorbedfromtheGITAdministeredorallyforthetreatmentofantibioticassociatedenterocolitiscausedbyC difficile 0 125 0 25gq6hrs99 excretedbyglomerularfiltrationT1 26 10days notremovedbydialysis SepsisorendocardititscausedbyMethicillinresistantstaphCombinedwithCefotaxime CeftriaxoneorRifampicinforthetreatmentofmeningitissuspectedorknowntobecausedbyahighlypenicillinresistantstrainofpneumococcus Recommendeddosageis30mg kg dayintwoorthreedivideddoses Adultswithnormalrenalfunction 1gevery12hrsChildren 40mg kg din3to4divideddose Causesphlebitis chillsandfever ototoxicity nephrotoxicity redmanorrednecksyndrome 2 FOSFOMYCIN inhibitsaveryearlystageofbacterialcellwallsynthesis inhibitscytoplasmicenzymeenolpyruvatetransferasebycovalentlybindingtothecysteineresidueoftheactivesiteandblockingthephosphoenolpyruvatetoUDP N acetylglucosamine 1ststepintheformationofUDP N acetylmuramicacid theprecursorofacetylmuramicacid foundonlyinbacterialcellwalls Drugistransportedintothecellbyglycerophosphateorglucose6phosphatetransportsystems Resistanceisduetoinadequatetransportofdrugintothecell ActiveagainstbothGram andGram Invitrosynergismwithbetalactams aminoglycosidesorfluoroquinolones Availableorally 2 4g singledoseinuncomplicatedUTI andparenterally Excretedthroughthekidneys Safeinpregnancy 4 BACITRACIN cyclicpeptidemixture activeagainstGram organisms inhibitscellwallformationbyinterferingwithdephosphorylation incyclingofthelipidcarrierthattransferspeptidoclycansubunitstothegrowingcellwallnephrotoxic poorlyabsorbed limitedtotopicaluse500units gointment PolymyxinBorNeomycin 5 CYCLOSERINE watersoluble veryunstableatacidphtreattuberculosiscausedbyM tuberculosisresistanttofirstlineagents structuralanalogsofD alanineandinhibitsincorporationofD alanineintopeptidoglycanpentapeptidebyinhibitingalanineracemasewhichconvertsLalaninetoDalanineandD alanyl D alanineligase widelydistributedintotissues excretedthroughtheurine 0 5 1g din2 3divideddoses causesdoserelatedCNStoxicity headaches tremors acutepsychocis convulsions THANKYOUVERYMUCHANDSTUDYWELL PROTEINSYNTHESISINHIBITORSMa ShielaCano Guiking M D The30SInhibitors I AMINOGLYCOSIDESOlderAminoglycosides StreptomycinKanamycinNewerAminoglycosides GentamicinTobramycinNeomycinAmikacinNetilmicinSisomicin AntimicrobialSpectrum 1 Gram AerobicBacilli2 Beta lactamaseproducers Staph aureusN gonorrhea3 MycobacteriaMechanismofAction interfereswithinitiationcomplexofpeptideformation inducesmisreadingofmRNAcausingincorporationofincorrectAAcausesbreakupofpolysomesintononfunctionalmonosomes Requiresoxygenuptake thereforeineffectiveagainstanaerobes Bactericidal MicrobialResistance 1 enzymeinactivation2 Cellsurfacealteration3 receptorproteinalteration4 oxygenrequirementrelatedKinetics minimallyabsorbedfromtheGIT wellabsorbedthruIM IVpoorlypenetratetheBBBnotsignificantlymetabolizedprimarilyexecutedunchangedthroughGFClinicalUses severegram rodinfectionsMycobacterialinfections Toxicity Ototoxicity esp withloopdiuretics Auditorydamage Neomycin KanamycinandAmikacinVestibularDamage Streptomycin GentamicinNephrotoxicity esp withcephalosporins Neomycin Tobramycin Gentamicin mostnephrotoxic STREPTOMYCIN ribosomalresistancetothisagentdevelopsreadily limitingitsroleasasingleagent mainlyusedasasecondlineagentfortreatmentoftuberculosis givenat0 5 1g d 7 5 15mg kg dayforchildren IMorIVshouldbeusedonlyincombinationwithotheragentstopreventemergenceofresistance Inplague tularemiaandsometimesbrucellosis 1g d 15mg kg dayforchildren IMorIV oraltetracycline Penicillin effectiveforenterococcalendocarditisand2weektherapyofviridansstreptococcalendocarditis Cancausefever skinrashesandotherallergicreactions painatinjectionsite vestibulardysfunction mostserioustoxiceffectIfgivenduringpregnancy cancausedeafnessinthenewborn GENTAMICINemployedmainlyinsevereinfections sepsisandpneumonia causedbygram bacteriaincombinationwithacephalosporinorapenicillinmaybelifesavinggivenat5 6mg kg dayIVinthreeequaldoses PenicillinGforbactericidalactivityinendocarditisduetoviridansstreptococciorenterococciandincombinationwithNafcillininselectedcasesofstaphylococcalendocarditisSerumconcentrationsandrenalfunctionshouldbemonitoredifadministeredformorethanafewdaysorifrenalfunctionischanging eg Sepsis oftencomplicatedbyacuterenalfailure Gentamicinsulfate0 1 0 3 cream ointment forthetreatmentofinfectedburns wounds orskinlesionsandthepreventionofintravenouscatheterinfectionsTopicalgentamicinispartlyinactivatedbypurulentexudatesTenmilligramscanbeinjectedsubconjunctivallyfortreatmentofocularinfections Nephrotoxicityisreversibleandusuallymild Irreversibleototoxicitymanifestedasvestibulardysfunction hypersensitivityreactionsareuncommon TOBRAMYCINAntimicrobialspectrumandpharmacokineticpropertiesvirtuallyidenticaltogentamicinGivenat5 6mg kgIMorIVintothreeequalamountsq8hoursBloodlevelsshouldbemonitoredinrenalinsufficiencySlightlymoreactiveagainstpseudomonasbutnotE faeciumOtotoxicandnephrotoxic AMIKACINsemisyntheticderivativeofkanamycinresistanttomanyinactivatingenzymesfortuberculosis givenat7 5 15mg kg dasaoncedailyor2 3xweeklySerumconcentrationsshouldbemonitoredNephrotoxicandototoxic NETILMICINsharesmanycharacteristicswithgentamicinandtobramycindosageandtheroutesofadministrationarethesame completelytherapeuticallyinterchangeablewithgentamicinorto